This invention relates to a process for preparing bicyclic, .beta.-lactam antibiotics. Specifically it relates to preparing 6- and 2-substituted-1-carbadethiapen-2-em-3-caboxylic acids and their pharmaceutically acceptable salts and esters (I): ##STR3## wherein, inter alia, R.sup.1 and R.sup.2 are independently selected from hydrogen, substituted and unsubstituted: alkyl, aryl, aralkyl, and R.sup.3 is inter alia, selected from hydrogen, --R, --OR, --SR,; wherein R is substituted and unsubstituted: alkyl, aryl and aralkyl.
In general, the process of this invention provides the substituted carbapenem (I) via a transition metal carbonyl complex induced ring closure and carbonyl insertion of an appropriately substituted aminoalkene. This general reaction has been reported in the literature for the preparation of the unsubstituted, antibiotically inactive bicyclic .beta.-lactams 4 and 7 [Wong, et al., J.A.C.S. 99 2823, (1977)]: ##STR4## wherein: F.sub.p =.eta..sup.5 --C.sub.5 H.sub.5 Fe(CO).sub.2. In the Wong, et al., scheme, the complex 2 is obtained from the olefinic amine by exchange reaction with F.sub.p (isobutene)tetrafluoroborate. Successive deprotonation with tri-n-butylamine followed by potassium tert-butoxide gives the piperidine complex 3, which is coverted with Ag.sub.2 O (THF, 65.degree. C., 20 h) to the lactam 4.
A similar sequence, employing 1-pentenylammonium tetrafluoroborate gives the pyrrolidine complex 5. An attempt to convert this directly to .beta.-lactam by oxidation led instead to a polyamide (v.sub.CO 1590 cm.sup.-1) due to the high reactivity of this lactam. However, when 5 was heated in THF for 4 h in the presence of 10 molar % of triphenylphosphine it was smoothly converted to the chelate 6 in 80% yield. Treatment of 6 with freshly precipitated Ag.sub.2 O for 5 min. at 25.degree. C. led to the disappearance of chelate carbonyl absorptions and formation of .beta.-lactam 7.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics and processes for their preparation continues.
Thus, it is an object of the present invention to provide a process for preparing the above-described carbapenems which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella.